A new class of weight-loss drug has shown it can significantly boost weight loss when paired with GLP-1 therapy – without adding side effects – in a mid-stage clinical trial, pointing to a powerful new combination approach to tackling obesity.
GLP-1 weight-loss drugs like semaglutide have taken the world by storm, but some studies have raised concerns about side effects, including kidney injury and skeletal muscle wastage. They’re also known to cause gastrointestinal side effects.
Nimacimab, a new type of anti-obesity drug with a different mode of action – it targets the body’s endocannabinoid system – has shown promising results in a Phase 2a clinical trial, significantly boosting weight loss when combined with a GLP-1 drug, and doing so without causing added side effects.
“This is the first clinical study to show that the combination of a CB1 inhibitor and a GLP-1 therapeutic can drive clinically meaningful additional weight loss beyond a GLP-1 drug alone,” said Louis Aronne, MD, past President of The Obesity Society and clinical advisor to Skye Bioscience, nimacimab’s developers. “Equally important, although the sample size is small, nimacimab achieved this without neuropsychiatric or additive gastrointestinal adverse events. I believe these results warrant further evaluation of the therapeutic potential of this novel CB1 inhibitor.”
The 26-week CBeyond study tested the drug, a first-in-class monoclonal antibody that blocks the CB1 receptors, either alone or alongside semaglutide (the active ingredient in Wegovy). The CB1 receptor is part of the body’s endocannabinoid system, which regulates appetite, metabolism, and fat storage. Overactivation of CB1 receptors can promote weight gain and fat accumulation. Older CB1-blocking drugs were abandoned due to psychiatric side effects, but nimacimab is engineered to stay outside the brain, potentially avoiding these problems.
In the trial, 136 adults with overweight or obesity were randomly assigned to receive weekly injections of nimacimab, semaglutide, both drugs together, or placebo. Participants who received nimacimab alone lost 1.5% of their body weight compared to 0.26% for placebo, a difference that was not statistically significant. However, pharmacokinetic data, which show how the body interacts with an administered substance, suggested that drug exposure was lower than expected at the 200 mg dose, indicating that higher doses may be more effective.
“The 200 mg monotherapy arm provided important pharmacokinetic insight, showing that lower-than-expected drug exposure may have limited the observed effect and informing the dose-ranging strategy we are developing,” said Puneet Arora, MD, Skye’s Chief Medical Office. “At the same time, the combination of nimacimab with semaglutide produced a clinically meaningful additional weight loss that exceeded semaglutide alone, with a favorable tolerability profile even in patients who achieved the highest exposure levels.”
Wikimedia Commons / Hua et al. (public domain)
As Arora said, the most striking results came from the combination arm. Participants who received both nimacimab and semaglutide lost an average of 13.2% of their body weight over 26 weeks, compared with 10.25% for those on semaglutide alone, a statistically significant difference of nearly 3%. Importantly, weight loss was still ongoing at the end of the study, suggesting additional reductions may be possible with longer treatment.
More patients in the combination group reached clinically meaningful weight-loss milestones: 100% lost more than 5% of their body weight (versus 85% with semaglutide alone), and 67% lost more than 10% (versus 50%). The combination also produced a healthier lean-to-fat mass ratio, indicating the weight loss was primarily due to fat reduction rather than muscle loss.
“With our preclinical data, toxicology safety margin, and PK [pharmacokinetic] modeling, we believe we have a path to support higher dosing, and we are evaluating the next stage of development to optimize dosing in potential future clinical trials,” said Arora.
Safety results were encouraging across all treatment arms. No neuropsychiatric side effects – such as anxiety, depression, or insomnia – were observed with nimacimab, either alone or in combination. Gastrointestinal side effects, a leading cause of discontinuation for GLP-1 therapies, were not increased by adding nimacimab to semaglutide.
The overall discontinuation rate was 27%, with only 3.7% of participants dropping out due to adverse events, most of which occurred in the placebo group.
“Gastrointestinal side effects remain a leading cause of discontinuation with obesity therapies,” said Sean Wharton, MD, Director of the Wharton Medical Clinic and a clinical advisor to Skye. “It was notable that nimacimab did not increase GI adverse events while adding clinically meaningful weight loss in combination with semaglutide. In my view, a next study with higher nimacimab dosing is the logical step to fully define its role in clinical practice.”
The promising combination results, coupled with a clean safety profile, support further clinical development of nimacimab, including trials with higher doses and longer treatment durations. Participants from the Phase 2a study are now continuing in a 26-week extension trial, with results expected in early 2026.
Source: Skye Bioscience
